Born in Madrid, Negredo started his career at Rayo Vallecano, making his professional debut in early 2005 with the club in the Segunda División B.

He did manage to impress first-team coach Fabio Capello and was called up for a few games in the Copa del Rey, but remained an unused substitute.

[27] Negredo was a regular first choice in the 2010–11 campaign, scoring 26 times in all competitions, 20 in the league (Fabiano also returned to São Paulo FC in March 2011).

[34] He scored all of his team's goals on the last day of the season, a 4–3 defeat of Valencia CF also at the Ramón Sánchez Pizjuán Stadium, clinching the Zarra Trophy in the process.

[38] Negredo made his Premier League debut on 19 August 2013, coming on as a substitute for countryman David Silva in a 4–0 home win against Newcastle United.

[46] On 1 September 2014, Negredo signed a loan deal with Valencia, which included an obligatory clause to buy his rights at the end of the campaign for a club record amount believed to be around €27 million.

[50] On 25 August, he helped his team to reach the Champions League group phase by scoring in the fourth minute of an eventual 2–1 loss at AS Monaco FC (4–3 on aggregate).

[55] On 20 July 2016, Negredo returned to the Premier League by joining Middlesbrough on a season-long loan,[56] accompanying several compatriots including manager Aitor Karanka.

[63] During his first weeks, he failed to establish his place in the starting eleven due to the good form of Cenk Tosun, who was sold to Everton in the winter transfer window.

[67] His maiden appearance in the UAE Pro League took place three days later, and he missed a penalty late into a 3–0 home loss to Al Ain FC.

[68] Negredo scored in the first minute of the final of the UAE League Cup against Shabab Al-Ahli Dubai FC on 17 January 2020, eventually helping his team to win their second title in the competition after the 2–1 victory.

[74] He and Anthony Lozano were the joint top scorers for the campaign with seven goals each, as they avoided relegation by one point;[75] his minutes were enough to add another year to his link by March.

[81][82] On 6 October 2009, Negredo received his first call to the Spain senior team, for a 2010 FIFA World Cup qualifier against Armenia on the 10th, following the injuries of David Villa and Daniel Güiza.

[84] Four days later, Negredo started and scored twice – also providing two assists – in another away fixture, at Bosnia and Herzegovina (5–2 triumph), as Spain eventually won all ten group matches.

Although he was regarded as a static forward, he was also known for his powerful striking ability with his left foot and his strength in the air, and was also capable of dropping into deeper positions in order to link-up with the midfielders.